1. Field of the Invention
This invention relates to a series of benzimidazole, pyridineimidazole, pyrazineimidiazole pyrimidineimidazole, pyridazineimidazole, and triazineimidazole derivatives which are selective inhibitors of the cyclic guanosine 3',5'-monophosphate phosphodiesterase enzyme ("cGMP PDE"), having utility in a variety of therapeutic areas including, for example, the treatment of cardiovascular disorders such as stable-, unstable- and variant-angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, thrombosis, glaucoma, sexual dysfunction, asthma (all pathological states which result in the elevation of intracellular levels of GMP) and any other disease condition related to the inhibition of cGMP PDE.
2. Related Background Art
Cyclic nucleotides are involved in regulating the activity of many cells in the airways, including pro-inflammatory, immunocompetent cells such as macrophages, eosinophils, mast cells and lymphocytes, and airway smooth muscle. Cyclic nucleotides that have been identified include cyclic adenosine 3',5'-monophosphate ("cAMP") and cyclic guanoside 3',5'-monophosphate ("cGMP"). Cyclic nucleotides are inactivated by the action of cyclic nucleotide phosphodiesterase enzymes ("PDEs"). Multiple molecular forms of PDEs are present in mammalian cells. At least five different families have been identified. These families differ with respect to substrate specificity, intracellular location, sensitivity to inhibitors, and mode of regulation.
Cyclic guanoside 3',5'-monophosphate phosphodiesterase ("cGMP PDE") is responsible for inactivation of cGMP by catalyzizing the hydrolysis of 3'-ribose phosphate bond of cGMP as shown in Scheme 1. ##STR3## Scheme 1. Hydrolysis of the 3'-ribose phosphate bond of cGMP by cGMP PDE resulting in the formation of GMP.
Selective inhibition of cGMP PDE results in elevation of cGMP levels, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic and vasodilatory activity. Thus such inhibitors of the cGMP PDE have utility in the treatment of diseases such as stable-, unstable- and variant-angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, thrombosis, glaucoma, impotence, asthma (all pathological states which result in the elevation of intracellular levels of GMP) and any other disease condition related to the inhibition of cGMP PDE. It has been shown that selective inhibitors of cGMP PDE lower mean arterial blood pressure and promote sodium excretion in an anesthetized rat (E. G. McMahon et al., J. Pharmacol. Exp. Ther. 251, 1000-1005, 1989). Accordingly, inhibitors of cGMP PDE are potentially potent drugs for use in treating a wide variety of circulatory type disorders.
Some efforts have been made to develop cGMP PDE inhibitors. For example, a number of pyrido[3,2-d]pyrimidin-4-one derivatives have been disclosed in the prior art as cGMP PDE inhibitors. In particular, PCT International Publication No. WO 94/05661 discloses a series of pyrido[3,2-d]pyrimidin-4-ones containing a 2,5-disubstituted phenyl moiety at the 2 position of the pyrido[3,2-d]pyrimidin-4-one bicyclic system as selective inhibitors of cGMP PDE over cAMP PDE. In European patent application No. EP-A-0347146 another series of pyrido[3,2-d]pyrimidin-4-one phosphodiesterase inhibitors having a monosubstituted phenyl moiety at the 2-position of the hetrocyclicbicyclic ring system were disclosed. In U.S. Pat. No. 5,576,322 a series of 2,4-diaminoquinazoline compounds are disclosed as cGMP PDE inhibitors.
The identification of additional potent and selective cGMP PDE inhibitors is highly desirable. This invention provides a series of benzimidazole, pyridineimidazole, pyrazineimidiazole pyrimidineimidazole, pyridazineimidazole, and triazineimidazole derivatives which are selective inhibitors of cGMP PDE. The disclosed cGMP PDE inhibitors are useful in the treatment of a variety of cardiovascular disorders.